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Comparison of the Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Three Different Formulations of Intravenous Epoprostenol Sodium

L. Nicolas

M. Gutierrez

J. Dingemanse

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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

Nicolas L, Gutierrez M, Dingemanse J

Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.

BACKGROUNDA change in excipient of epoprostenol sodium, an i.v. pulmonary arterial hypertension treatment, from glycine-mannitol (epoprostenol GM; Flolan®) to arginine-mannitol (epoprostenol AM; Veletri®) or to undisclosed excipients (epoprostenol XX) has led to improvements in stability of the latter two formulations.

METHODS: The pharmacokinetic (PK), hemodynamic, safety, and tolerability profiles of these formulations were compared in this 2-part study. Twenty healthy males in Part 1 and 20 different patients in Part 2 received epoprostenol AM and epoprostenol XX, and epoprostenol GM and epoprostenol XX, respectively, in a crossover design of sequential 2h i.v. infusions of 2, 4, 6 and 8 ng/kg/min. PK profiles were assessed by analyzing plasma concentration-time curves of the primary epoprostenol metabolites 6-keto-prostacyclin F1α (kPF) and 6,15-diketo-13,14-dihydro-prostacyclin F1α (ddPF) obtained after treatment with the different epoprostenol formulations.

RESULTSFor Part 1, the ratio of the geometric means (90% CI) of AUC0-∞ calculated after epoprostenol AM and epoprostenol XX treatment was 0.91 (0.88–0.95) for kPF and 0.88 (0.84–0.92) for ddPF. For Part 2, the ratio of AUC0-∞ determined after epoprostenol GM and epoprostenol XX treatment was 0.97 (0.91–1.03) for kPF and 1.08 (1.02–1.14) for ddPF.

Hemodynamic variables, assessed by echocardiography, showed similar increases in cardiac output, cardiac index, and heart rate for all formulations with maximum values attained after 6–8h. Almost all subjects reported at least 1 adverse event.

CONCLUSIONThese results suggest the 3 formulations of i.v. epoprostenol sodium have the same PK, hemodynamic, safety, and tolerability profiles.